TARGETING LATS1/2 AND THE HIPPO INTRACELLULAR SIGNALING PATHWAY FOR CANCER IMMUNOTHERAPY

摘要

Provided are tumor cells having reduced or eliminated expression and/or activity of one or more proteins within or associated with the HIPPO intracellular signaling selected from the group consisting of large tumor suppressor kinase 1 (LATS1), large tumor suppressor kinase 2 (LATS2), serine/threonine kinase 4 (STK4) and a MAP4K family kinase (e.g., MAP4K1/2/3/4/5/6/7), as well as extracellular vesicles and cell lysates from such tumor cells. The tumor cells may also have reduced or eliminated expression and/or activity of serine/threonine kinase 3 (STK3) and/or overexpress one or both of YAP and/or TAZ, or hyperactive mutants thereof. Further provided are methods of inducing, promoting and/or enhancing an immune response against a tumor in a subject by administering tumor cells having reduced or eliminated expression and/or activity of one or more proteins within or associated with the HIPPO intracellular signaling selected from the group consisting of large tumor suppressor kinase 1 (LATS1), large tumor suppressor kinase 2 (LATS2), serine/threonine kinase 4 (STK4) and a MAP4K family kinase (e.g., MAP4K1/2/3/4/5/6/7), or extracellular vesicles or cell lysates of such tumor cells. Further provided are methods of inducing, promoting and/or enhancing an immune response against a tumor in a subject by administering inhibitors of expression and/or activity of one or more proteins within or associated with the HIPPO intracellular signaling selected from the group consisting of large tumor suppressor kinase 1 (LATS1), large tumor suppressor kinase 2 (LATS2), serine/threonine kinase 4 (STK4) and a MAP4K family kinase (e.g., MAP4K1/2/3/4/5/6/7), and optionally further inhibiting the expression and/or activity of serine/threonine kinase 3 (STK3).